Monday, January 12, 2009

Notes on Maguire interview on StutterTalk

Ora sent me his detailed notes on the Maguire interview on StutterTalk: see here. I briefly reported on the interview here. Jerry Maguire is involved in the Pagoclone trials. I visited him some time ago at the opening of his centre: see here.

[These are Ora’s notes, not a transcript]

Maguire: In the past, not much attention to was devoted to medical therapies for stuttering. In the 70s people tried using some of the older meds for schizophrenia such as haldoperidol – shown to at least reduce stuttering symptoms. But side effects were pretty great.

Things lay fallow for a couple of decades.

More recently people have have explored dopamine blockers. Dopamine is involved in movement, and they also believe it’s involved in speech. They notice that stuttering particularly affects the beginning of the word. The theory is that by lowering dopamine levels in the brain, you can improve the timing and the initiation of speech. Those medications were developed for schizophrenia and bipolar disorder (not that there’s any relation between schizophrenia/BP disorder and stuttering, just that the same neurotransmitter affects both). The original idea for the use of these medications in stuttering was spawned by the fact that Tourette’s syndrome looks similar to stuttering: also, they both begin in childhood, they have a male-to-female ratio that’s very similar.

Risperdal (risperidone) was the first of these new generation of dopamine blocking medications. They studied it and found it to be effective. It reduced stuttering symptoms by 40-60%, in some individuals even higher. Tolerated pretty well; they did see some potential side effects. It can raise prolactin, which may cause sexual dysfunction. Some weight gain, milder amounts of weight gain. In higher doses than they used, such as the dosages used for bipolar disorder, it can cause muscle rigidity, even tardive dyskinesia. Potentially long-term studies should be done. (The dosage that they studied was 0.5 – 2 mg / day.)

These studies led to another compound called olanzapine (Zyprexa), developed in mid-late 90s for schizophrenia and bipolar disorder. They did a double-blind placebo-controlled study, found it to be effective for stuttering, reducing stuttering symptoms in the majority of individuals treated – up to 70% reduction in 70% of the patients. The side effects: it caused an appetite increase in many/most of the individuals, leading to weight gain. The most concerning side effect in at-risk individuals is the potential for diabetes.

Maguire himself tolerated risperidone quite well for about two years, then switched over to olanzapine for about ten years. Did have some weight gain – about 20 pounds – but he was between ages of 30 and 40, stopped exercising, got married, so it’s hard to tell the cause of the weight gain.

Recently there are medications which work on the dopamine system but do not have the weight gains or metabolic concerns associated with olanzapine, at least in adults. He’s just published a case report on Abilify (aripiprazole) – another medication for schizophrenia and bipolar disorder. It’s a partial dopamine blocker, so it may even work better at lower dosage. A weight-neutral compound. They’re really excited about it.

Maguire is now on ziprasidone (Geodon). Also a dopamine blocker. Weight neutral. Does have some potential, very rarely, for heart conduction problems, so an EKG is needed beforehand.

He’s a firm believer that these medications would work better with speech therapy – synergistic effect. They’ve seen that effect with other disorders of the brain such as OCD and major depressive disorder, that they work better when the medication is combined with the therapy, than with the medication alone. The medications are not a complete cure; they don’t work in everyone, and it’s not a complete effect.

These medications are not going to totally remove the stuttering. He finds that the types of stuttering where it’s most beneficial is for people who have secondary characteristics (eye blinks, facial grimaces). He hasn’t studied it much so well, but in the patients he’s treated, that’s what he’s observed.

Of course, they’re using medications that are “borrowed” from another condition (schizophrenia / bipolar disorder). With pagoclone, now in clinical trials, they now have a medication that is not borrowed in that way. It’s completed Phase II trials. Originally derived as an anti-anxiety agent. It doesn’t work on the dopamine system, but on the GABA system, which is involved in the anxiety response. (It’s known that the stuttering syndrome has a component of anxiety, but stuttering is not caused by anxiety.) It’s tolerated very well; so far it’s been prescribed in over 1000 individuals (thousands?0 – 100+ for stuttering, but over 1000 for other disorders. Appears to be tolerated much better than the dopamine-blocking medications. Their theory is that it’s a back-door way to modify dopamine. It may be a safer way than the dopamine blockers, with the added benefit that it reduces anxiety. The greatest benefit of pagoclone its tolerability. Tolerability appears to be very high, the side effects appear to be very low, just a little sedation and headaches.

Looks like the Phase III pagoclone study will start pretty soon. (They’ve finalized the research article. They presented at the Oxford dysfluency conference.) The next pagoclone study will likely have centers around the US. [OM note: since the date of the interview, they’ve announced that they’ll be doing Phase II-b studies, not Phase III immediately.]

With pagoclone they’ve seen 20-40% efficacy [unclear if he meant 20-40% of individuals or 20-40% reduction in symptoms], but they’ve seen individual respond up to 80% reduction in symptons, In general, Phase II trials may not see the full effect size because they’re using one fixed dose. In the next phase they’ll try a range of doses. In Phase III they’ll test in more individuals and then tune the dose, and even increasing the length of the double-blind phase, because with pagoclone it appears that the longer you stay on the medication, the greater the effect.

Interviewer: We know that with speech therapies they often work well at the beginning but the benefits reduce after a while. What about these medications?

Maguire: For the dopamine blocking medications I’ve been discussing today there’s been a persistence of effect. At times they’ve observed what they think is of a recalibration of the receptors in the brain, so that may had to increase the dosage over time, though rarely. In the open-label phase of pagoclone, the response tends to be persistent. Not everyone responds, but for people who do respond, the response tends to be persistent. Also, pagoclone seems to not affect the naturalness of speech. (Interviewer: this is a common deterrent to maintaining the benefits of speech therapies; people sometimes prefer stuttering to unnatural speech.)

Maguire is not on pagoclone because FDA rules bar an investigator from being on the medication that he’s studying.

Interviewer: Other drugs? One researcher has reported on a “cocktail” of citalopram (Celexa), clomipramine (Anafranil) and alprazolam (Xanax ) for a small group (three people?)

Maguire: That makes sense in that works on GABA, but the problem with Zanax is that there’s a tolerance built up, so that an initial effective dose of 0.5 mg may have to be increased to 1 or 2 mg in a month or two. A tolerance is built up; risk of addition. (The good thing about pagaclone is that it appears not to have an addictive effect.)

Citalopram (Celexa), an antidepressant, works on the serotonin system. It may decrease the social anxiety of stuttering.

Clomimpramine is a tricyclic antidepressant and it does have a dopamine effect. But it’s got side effects, such as constipation, light-headedness. Also, sexual dysfunction, even higher than risperdal.

One thing he’s concerned about in general: that people are going to read about these drugs and try them, but at a too-high dose, because the standard doses are calibrated for schizophrenia.

For the drug that he’s taking, ziprasidone (Geodon), his dosage is about 1/8 the typical dose for bipolar disorder.

Maguire’s recommendation: combine medical therapy with a well-qualified speech-language therapist. His center at University of California at Irvine has received a grant where they can provide consultations via telemedicine to people anywhere in the world. People need a webcam and a high-speed Internet connection. Consultation over the Internet, then work with people’s own physician and monitor the level of care. He’d like to set up a number of centers where people could work both with speech therapists locally and with his center in California for the drug therapies, or even vice versa, with his patients in California working with speech therapists remotely. He knows a lot about the medication, but has no expertise in speech language pathology, except for his own personal therapy for his own stuttering. But there’s lot more to the stuttering person than the medical aspect, and he’d like to collaborate with people who use different treatments. Monotherapy (such as drug therapy) may work in some people, but will it persist? He thinks the best approach is a multimodal approach combining drug therapy and behavioral study. (And the interviewer (Greg) added: and perhaps prosthetic devices. [Does he mean masking devices such as SpeechEasy?])

6 comments:

I'm not too sure about the link between stuttering and Tourette's ... the link may be circumstantial; is there any concrete evidence of a link?

About stuttering medication: A lot of stutterers (maybe most stutterers) report improved fluency when they have drunk too much alcohol. Alcohol reduces inhibitions and anxiety, which are both detrimental to a stutterer's fluency. So we might call excessive alcohol a cure for stuttering - but we can't because of it's side-effects.

A few years ago I accidentally took a friend's antidepressant medication (I mistook it for one of my vitamin tablets). The effect was incredible; I felt no anxiety (I almost felt reckless) and my fluency improved a lot ... I was almost perfectly fluent for the next 2 days. It just proved to me how much anxiety contributes to my stutter. It wouldn't come as a surprise of a pagoclone (or some other kind of anti-anxiety drug) might improve fluency.

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